Overview
teSarcopenia is a disease that causes the gradual loss of muscle mass, strength, and function that occurs as a natural part of the aging process. Despite the severity of Sarcopenia, there is no proper treatment for Sarcopenia currently. Thus, we proposed Sarcotreat, a Life biotherapeutic product based on the concept of the gut-muscle axis. The gut-muscle axis explains the importance of good microbiota to make muscle better growth.xt
What is Sarcopenia?
Sarcopenia is a medical term used to describe the gradual loss of muscle mass, strength, and function that occurs as a natural part of the aging process. However, the disease lacks a more precise and unified definition. In this study, team PTSH-Taiwan chose the sarcopenia definition indicated by the European Working Group on Sarcopenia in Older People (EWGSOP), which is the most well-known organization for sarcopenia prevention and treatment. According to the organization, sarcopenia is characterized by Low muscle strength, Low muscle quantity or quality, and Low physical performance.
Secondly, sarcopenia is a multi-causal disease. It results from a combination of factors including hormonal changes, a reduction of muscle capillaries, a decrease in insulin sensitivity, reduced physical activity, nutritional deficiency, protein synthesis disruption, and other underlying health conditions. People tend to experience a decrease in muscle protein synthesis and an increase in muscle breakdown, or even degradation of mitochondria. All of the above can ultimately lead to a decline in muscle mass. Moreover, Sarcopenia affects the musculoskeletal system, leading to increased frailty and a heightened vulnerability to falls and fractures. These outcomes often necessitate hospitalizations and surgical interventions, consequently raising the risk of complications, including mortality.
Current treatment
Current primary treatments encompass non-pharmacological approaches such as exercise and dietary adjustments, as well as hormone therapy. However, they are ineffective, inefficient, and come with certain risks. Exercise, for instance, hardly works for people with disabilities. Physical intervention, according to our interview with doctors, has shown only marginal effects in improving sarcopenia. Drugs used in supportive therapies usually have strong adverse side effects. Moreover, specific drugs designed to treat sarcopenia are conspicuously absent from the medical arsenal. Hence, team PTSH-Taiwan is dedicated to developing a more efficient sarcopenia medication, Sarcotreat, that promises improved outcomes for patients and greater accessibility to those in need.
Gut-muscle axis
The gut-muscle axis highlights the significant impact of the gut microbiome on muscle synthesis. Sarcopenia and systemic weakness among the elderly have been correlated with intestinal dysbiosis, contributing to increased intestinal barrier permeability, elevated blood LPS levels, activation of the immune system, and a reduction of insulin sensitivity. An unhealthy diet and an imbalanced gut microbiome can lead to increased inflammation, immune system dysregulation, and disruptions in muscle protein synthesis, mitochondrial function, muscle glycogen storage, and accumulation of body fat. Therefore, optimizing gut microbiome composition becomes crucial. A well-balanced microbiome can reduce inflammatory markers and limit the production of reactive oxygen species, thus minimizing damage to macromolecules. Moreover, animal studies clearly emphasize the reduction of muscle atrophy markers. Hence, we believe using potential probiotics, Kluyveromyces marxianus, Bacillus subtilis, and Clostridium butyricum, as vectors of drug delivery can further enhance the efficacy of Sarcotreat.
Live-biotherapeutic product
A live-biotherapeutic product (LBP) is a biological product containing live organisms, designed for the prevention, treatment, or cure of human diseases or conditions. The growing understanding of the microbiota's role in health and disease has expanded the potential applications of probiotic interventions, which can be marketed as food, food supplements, or drugs depending on their intended use. This year, we are developing a live biotherapeutic product that delivers drugs to human in the gut to treat sarcopenia.
Five chemicals
Below are the five chemicals produced by the three vectors to treat sarcopenia.
| Chemicals | Function |
|---|---|
| Butyrate | Promote Muscle synthesis、 prevents muscle cell autophagy、anti-inflammation、prevent fat accumulation、increase insulin sensitivity、anti-fatigue |
| HMB | Promote muscle synthesis、prevent muscle cell autophagy |
| Astaxanthin | Promote muscle synthesis、prevent cellular oxidative damage、promote mitochondrial biosynthesis、prevention of fat accumulation、anti-fatigue, prevention of muscle cell autophagy |
| NMN | promote mitochondrial biosynthesis、promote whole-body metabolism, enhance aerobic capacity |
| PQQ | promote mitochondrial biosynthesis、increase mitochondrial efficiency |
Our solution
This year, team PTSH-Taiwan attempts to develop an engineered live biotherapeutic product that prevents and supports the treatment of sarcopenia with cocktail therapy. Here we present, Sarcotreat. Sarcotreat is a designed microbiome that consists of three microorganisms: Kluyveromyces marxianus, Bacillus subtilis, and Clostridium. They will produce five beneficial chemicals which are NMN, HMB, PQQ, astaxanthin, and butyrate in order to combat sarcopenia. Through gene editing, each of the microorganisms contains two major systems, an engineered secretion system and a kill switch system. Through engineering, the microorganisms will acquire NMN, astaxanthin, and HMB biosyntheitc pathway. Furthermore, we recognize that there are PQQ construct existing in iGEM registry, so we will not engineer PQQ biosynthetic pathway. Instead, we will incorporate thees already-existing design into our project. The secretion system ensures that the bacteria produce our target chemical, and the Kill switch system works when the organisms leak out of the body. In the absence of sulfur, the microorganisms cease to produce antitoxin and die. In our view, we believe that Sarcotreat is a groundbreaking product that can save millions of people's lives.
Reference
- Przewłócka, K., Folwarski, M., Kaźmierczak-Siedlecka, K., Skonieczna-Żydecka, K., & Kaczor, J. J. (2020). Gut-Muscle AxisExists and May Affect Skeletal Muscle Adaptation to Training. Nutrients, 12(5), 1451. https://doi.org/10.3390/nu12051451
Jang, J. Y., Kim, D., & Kim, N. D. (2023). Pathogenesis, Intervention, and Current Status of Drug Development for Sarcopenia: A Review. Biomedicines, 11(6), 1635. https://doi.org/10.3390/biomedicines11061635
- Lo, J. H., U, K. P., Yiu, T., Ong, M. T., & Lee, W. Y. (2020). Sarcopenia: Current treatments and new regenerative therapeutic approaches. Journal of orthopaedic translation, 23, 38–52. https://doi.org/10.1016/j.jot.2020.04.002
- Cruz-Jentoft, A. J., Bahat, G., Bauer, J., Boirie, Y., Bruyère, O., Cederholm, T., Cooper, C., Landi, F., Rolland, Y., Sayer, A. A., Schneider, S. M., Sieber, C. C., Topinkova, E., Vandewoude, M., Visser, M., Zamboni, M., & Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2 (2019). Sarcopenia: revised European consensus on definition and diagnosis. Age and ageing, 48(1), 16–31. https://doi.org/10.1093/ageing/afy169
- Cordaillat-Simmons, M., Rouanet, A., & Pot, B. (2020). Live biotherapeutic products: the importance of a defined regulatory framework. Experimental & molecular medicine, 52(9), 1397–1406. https://doi.org/10.1038/s12276-020-0437-6
- Cruz-Jentoft, A. J., Baeyens, J. P., Bauer, J. M., Boirie, Y., Cederholm, T., Landi, F., Martin, F. C., Michel, J. P., Rolland, Y., Schneider, S. M., Topinková, E., Vandewoude, M., Zamboni, M., & European Working Group on Sarcopenia in Older People (2010). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and ageing, 39(4), 412–423. https://doi.org/10.1093/ageing/afq034
- Cruz-Jentoft, A. J., Bahat, G., Bauer, J., Boirie, Y., Bruyère, O., Cederholm, T., Cooper, C., Landi, F., Rolland, Y., Sayer, A. A., Schneider, S. M., Sieber, C. C., Topinkova, E., Vandewoude, M., Visser, M., Zamboni, M., & Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2 (2019). Sarcopenia: revised European consensus on definition and diagnosis. Age and ageing, 48(1), 16–31. https://doi.org/10.1093/ageing/afy169